Glutamatergic synaptic transmission supports the rapid transfer of information between neurons in the mammalian CNS and undergoes changes in efficacy that may underlie memory storage and learning. An essential step in glutamatergic transmission involves removal of glutamate from the extracellular space by Na+-dependent transporters. Immunocytochemical, electrophysiological, and molecular/transgenic studies indicate that glutamate uptake by astroglial cells is critical for preventing the accumulation of glutamate, maintaining the sensitivity of receptors, and preserving the specificity of synaptic transmission. The close proximity of astrocyte processes to synapses and the high density of transporters in these membranes suggest that they may also shape the activation of receptors during first few milliseconds after release. This involvement of glutamate transporters in excitatory transmission raises new questions about how the activity of these transporters is regulated. We hypothesize that mechanisms exist to rapidly adjust the capacity of uptake to changes in glutamate release. We have shown that the activity of glutamate transporters can be monitored in astroglial cells in acute brain slices using electrophysiological techniques, providing the means to study the properties and regulation of these transporters in their native membranes. Studies in our laboratory indicate that activation of metabotropic glutamate receptors (mGluR) on hippocampal astrocytes triggers a dramatic enhancement of glutamate transporter currents in these cells. We propose to determine the mGluRs and transporters responsible for this enhancement, the mechanisms involved, and the consequences of this enhancement for glutamate clearance and receptor occupancy during synaptic transmission. These studies of the basic mechanisms of glutamate transporter regulation may reveal how the action of glutamate is constrained despite rapid and maintained changes in the activity of excitatory afferents. The dual role of glutamate as an excitatory transmitter and excitotoxin, suggests that glutamate transporters could be effective therapeutic targets in treating disorders of cognitive impairment, and in preventing neuronal damage associated with stroke and neurodegenerative diseases. Understanding the endogenous mechanisms of transporter regulation may thus provide us with new approaches for treating neurological diseases.